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A more recent version of this article appeared on March 5, 2004
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M312397200v1
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Papers In Press, published online ahead of print December 5, 2003
J. Biol. Chem, 10.1074/jbc.M312397200
Submitted on November 12, 2003
Revised on December 4, 2003
Accepted on December 5, 2003

Insulin promotes rat retinal neuronal cell survival in a p70S6K-dependent manner

Xiaohua Wu, Chad E. N. Reiter, David A. Antonetti, Scot R. Kimball, Leonard S. Jefferson, and Thomas W. Gardner

Ophthalmology, H166, Pennsylvania State University College of Medicine, Hershey, PA 17033

Corresponding Author: tgardner{at}psu.edu

The purpose of this study was to examine the role of the ribosomal protein S6 protein kinase (p70S6K), a protein synthesis regulator, in promoting retinal neuronal cell survival. Differentiated R28 rat retinal neuronal cells were used as an experimental model. Cells were maintained in DMEM supplemented with 10% new born calf serum, and during the period of experimentation were exposed either to the absence or presence of 10nM insulin. Insulin treatment induced p70S6K, mTOR, and Akt phosphorylation, effects that were completely prevented by the PI3K inhibitor, LY294002. Insulin-induced phosphorylation of p70S6K and mTOR was prevented by the mTOR inhibitor, rapamycin. Apoptosis, induced by serum deprivation and evaluated by Hoechst staining, was inhibited by insulin treatment in R28 cells, but not in L6 muscle cells. This effect of insulin was also largely prevented by rapamycin. Inhibition of p70S6K activity by exogenous expression of a dominant negative mutant of p70S6K prevented insulin-induced cell survival, whereas, overexpression of wildtype p70S6K or expression of a rapamycin resistant form of the kinase enhanced the effect of insulin on survival. Enhanced cell survival under the latter condition was accompanied by increased p70S6K activity and phosphorylation. Rapamycin did not inhibit insulin induced p70S6K phosphorylation and activity in cells transfected with the rapamycin resistant mutant. Together, these results suggest that p70S6K plays a key role in insulin stimulated retinal neuronal cell survival.


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